An important pathogenetic mechanism in Hodgkin lymphoma (HL) is the interaction between the neoplastic and reactive cells mediated by a complex network of cytokines with activation of cytokine signal transduction (STAT) pathways. We studied the prognostic impact of the phosphorylation status of STAT5 in HL. By using immunohistochemical analysis, we found phosphorylated STAT5 (pSTAT5) in 35 (38%) of 93 lymph node biopsy specimens of patients with HL. The detection of pSTAT5 in Hodgkin and Reed-Sternberg (HRS) cells in classical HL (cHL) was not associated with any clinical and biologic features evaluated, including Epstein-Barr virus status. The primary end point for analysis of clinical outcome was freedom from treatment failure (FFTF). At a median follow-up of 5 years, pSTAT5+ patients with cHL had a better FFTF than pSTAT5-patients (77% vs 56%; P = .03), which translated into a reduced risk for failure for pSTAT5+ patients with a hazard ratio of 0.2 (95% confidence interval, 0.06-0.73; P = .015). Our data suggest that the phosphorylation status of STAT5 of HRS cells in cHL could be a prognostic marker in HL.